• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    A novel method for the preparation of intermediates for pharmaceutically active quinolonecarboxylic acids in a single-step method.
    公开号:SU1660582A3
    申请号:SU88
    申请日:1988-07-20
    公开日:1991-06-30
    发明作者:Цербес Рудольф (De)；Цербес Рудольф；Прейсс Михаель (De)；Прейсс Михаель
    申请人:Байер Аг (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to methods for the preparation of 1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid (I), which is used as. an intermediate product in the synthesis of pharmaceutically active quinoline carboxylic acids.
    The purpose of the invention is to intensify the process while maintaining a high yield of the target product.
    The goal is achieved by the interaction of 2,4-dichloro-5-fluorobenzoyl chloride (II) with the compound
    CH-COORi
    sd-uik,
    where the same or different and mean lower alkyl, in the environment of a low-boiling organic solvent in the presence
    oa
    bases at 90-110 ° C or the boiling point of the reaction mixture, followed by interaction of the obtained intermediate with cyclopropylamine in an inert organic solvent at 70-90 ° C, followed by cyclization of the resulting intermediate in an inert high-boiling organic solvent at 135-145 ° C in the presence of a base, followed by saponification and precipitation of the target product with an acid, the process being carried out without isolation of the intermediate reaction products.
    Example 1. 28.8 g of ethyl ester of M, M-dimethylaminoacrylic acid and 26 g of NN-dimethylbenzylamine in 71 ml of toluene are heated to 90 ° C, and 40 g of dichloro-5-fluorobenzoyl chloride. Then it is further stirred for 15 minutes and the precipitated N.N-dimethylenebenzylamine hydrochloride is separated on a suction filter. The filtrate is evaporated in vacuo and the residue is mixed with 80 ml of butyl glycol. At 70-75 ° C, 13 g of cyclopropylamine are added dropwise within 30 minutes and after the addition the temperature of the reaction mixture is maintained at 100 ° C for 1 hour until the end of the evolution of gas, 27.9 g of potash and 100 ml are added to the reaction mixture butylglycol and slowly heated to 135-145 ° C. Thereby, about 40 ml of low boiling point components are distilled off. The temperature is maintained for 1.5 hours. Then it is cooled to 100-120 ° C and 130 ml of water are added to the reaction mixture. The mixture is stirred at 90 ° C for 15 minutes and 27 ml of acetic acid are added dropwise at this temperature for 15 minutes. The contents of the flask are cooled and the solid is separated on a suction filter. The product is washed with 27 ml of water and 50 ml of methanol, sucked off to dryness and dried in vacuum at 70 ° C for 24 h. 37 g (74.9% based on the starting benzoyl chloride) are obtained. 1-cyclopropyl-7-chloro-6 -fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, m.p. 240-241 ° C.
    Example 2. 43.2 g of N.N-dimethylamino-acrylicic acid ethyl ester in 84 ml of toluene are heated to 100 ° C and 40 ml of triethylamine are added.
    At the reflux temperature, 60 g of 2,4-dichloro-5-fluorobenzoyl chloride are added dropwise over 30 minutes and then the precipitated triethylamine hydrochloride is separated on a suction filter. Additionally washed with 55 ml of toluene and added dropwise to the filtrate within 20 minutes at 70 ° C, 16.2 g of cyclopropylamine, and then heated to 100 ° C until the end of the evolution of gas. Then 42 g of potash and 270 ml of butyl glycol are added and slowly heated to 135-145 ° C. With
    About 180 ml of toluene and low boiling components are distilled off. 8 for 1.5 hours, the temperature was maintained at 135-145 ° C and after cooling the reaction mixture to 100 ° C, 200 ml of water was added.
    0 After 15 minutes at 90 ° C, 40.5 ml of acetic acid is added dropwise and the precipitated solid is suction filtered on a suction filter. The product is additionally washed with 140 ml of water and 75 ml of methanol, sucked dry.
    5 and dried under vacuum for 24 hours at 70 ° C. 58.5 g (79%, calculated on the starting benzoyl chloride) of 1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo- are obtained. 3-quinoline carboxylic acid,
    0П р and м р 3. 44,7 complex ethyl
    N.N-dimethylaminoacrylic acid ester and 17.1 g of M, hG-dimethylpiperazine in 95 ml of cyclohexane are heated under reflux. Within 1 hour, 62 g of 2,4-dichloro-5-fluorobenzoyl chloride are added dropwise. The dimethylbenzylamine hydrochloride precipitated is separated on a suction filter and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in 125 ml of butylglycol and to a solution
    20.2 cyclopropylamine is added dropwise at 90 ° C. After the end of gas evolution, 43.4 potash and 165 ml of butyl glycol are added and heated to 145 ° C for 1.5 hours. In this case, a small amount of low-boiling components is first distilled. After 1.5 hours, cooled to 100 ° C, the reaction mixture is mixed with 205 ml of water and further stirred for 15 minutes at 95 ° C. 42 g of acetic acid are then added dropwise, cooled to 30 ° C, and the precipitated solid is distilled off on a suction filter. The filter cake is washed with 180 ml of water and 80 ml of 80% isopropanol and dried in vacuo overnight.
    5 at 70 ° C. 60.1 g (78.1%, calculated on the starting benzoyl chloride) of 1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are obtained. acid.
    Example 4. 33.7 g of the methyl ester of K, M-dimethylaminoacrylic acid and 40.5 g of M, G-dimethylbenzylamine in 95 ml of toluene are heated to 110 ° C. At a reflux temperature, 62 g 2,4-dichloro-5-fluorobenzoyl 5 chloride and then precipitated dimethylbenzylamine hydrochloride is separated on a suction filter,
    The solvent is distilled off in vacuo, 130 ml of butylglycol is added and 20.2 g of drops are added dropwise at 90 ° C over 20 minutes.
    cyclopropylamine. After the end of gas evolution, the reaction mixture is mixed with 43.4 g of potash and 150 ml of butyl glycol and slowly heated to 140 ° C, at the same time a small amount of low-boiling solvent is distilled off. Then additionally stirred for 1.5 hours at 140 ° C. After cooling to 100 ° C, 205 ml of water was added to the reaction mixture and stirred for 15 minutes at 90 ° C. Under mild cooling, 100 ml of 30% sulfuric acid are added, the solid is suction filtered on a suction filter and washed with 200 ml of water and 200 ml of isopropanol. The solid is dried under vacuum at 70 ° C. overnight. 59.4 j (77.2% in terms of the starting benzoylchloride) of 1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are obtained.
    EXAMPLE 5 To 55.7 g of tributylamine 55.6 g of cyclohexane ethyl ester of L, M-dimethylaminoacrylic acid in 95 ml of cyclohexane was added and 62 g of 2 were added dropwise at 85-95 ° C over 1 hour. , 4-dichloro-5-fluoro-benzoyl chloride. 250 ml of water are then added to the reaction mixture and the aqueous salt phase is separated. The aqueous phase is stirred together with 50 ml of cyclohexane and the combined organic phases are evaporated to dryness in a vacuum, obtained using a water-jet pump. The residue is taken up in 125 ml of butyl glycol, heated to 70 ° C, and 20.2 g of cyclopropylamine are added dropwise over 15 minutes. After gas evolution is complete, the next 160 ml of butyl glycol and 44 g of potash are added and the reaction mixture is slowly heated to 140 ° C. After reaching 140 ° C, it is further stirred for 1.5 hours, then cooled to 100 ° C, and 205 ml of water is added to the reaction mixture. After 15 minutes, 42 g of acetic acid are added dropwise over 10 minutes and cooled to room temperature. The precipitate is separated on a suction filter and washed with water and isopropanol. After drying in vacuo at 50 ° C overnight, 54.6 (71% in terms of the starting benzyl chloride) of 1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid are obtained. new acid
    Example 6 105 g of tributylamine and 86 g of N.N-dimethylaminoacrylic acid methyl ester in 148 ml of toluene are heated to 105 ° C and 124 g of 2,4-dichloro-5-fluorobenzoyl chloride is added dropwise over 1 hour. After cooling the reaction mixture to 50 ° C, it is extracted twice with 250 ml of water. The organic phase is concentrated in vacuo, obtained using a water-jet pump, and 7.5 g of cyclopropylamine is added to the residue at an internal temperature of 70-75 ° C. In this case, gaseous dimethylamine is released until the end of the reaction. The reaction mixture is mixed with 86.8 g of potash and 500 ml of butylglycol and slowly heated to 135-145 ° C. A small amount of the low boiling solvent is distilled off. The temperature is maintained at 135-145 ° C for 1.5 hours and then cooled to 100 ° C and 535 ml of 10% acetic acid are added. The resulting suspension is cooled to room temperature, the solid is distilled off on a suction filter and washed with 175 ml of water and 200 ml of 80% isopropanol. The product is dried overnight in vacuum at 70 ° C. 220 g (78.1% in terms of the starting benzoyl chloride) of 1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are obtained.
    The target product in examples 1-6 has so pl. 240-241 ° C, i.e., is highly pure. The first stage of the process can be carried out for no more than 75 minutes (instead of 5 hours by a known method) without deteriorating the yield of the final product due to the fact that benzoyl chloride is added to the mixture of acrylic ester, inert low boiling organic solvent and base at 90-110 ° C or its boiling point. This feature is significant, since the addition of acrylic acid ester to the mixture containing benzoyl chloride, the yield of the final product is significantly reduced. For example, by repeating Example 1, except that ethyl ester of L, M-dimethylaminoacrylic acid added to a mixture containing 2,4-dichloro-5-fluorobenzoyl chloride heated to 90 ° C, the yield of the target product is only 67.5%. Therefore, taking into account the exclusion of the proposed method, the loss of intermediate substances, the yield of the target product is practically below the level of the known method.
    Further intensification of the process is provided by carrying out a cyclization stage at 135-145 ° C in an environment of a high-boiling organic solvent. When this cyclization can be carried out for 90 minutes, whereas by a known method, it requires 180 minutes
    权利要求:
    Claims (5)
    [1]
    1. Method for preparing 1-cyclopropyl-7-chloro-6-fluoro-1, 4-dihydro-4-oxo-3-quinoline carboxylic acid of formula I
    Cun
    the interaction of the compounds of formula II
    C1 /
    C6C1 C1
    with a compound of general formula III10
    CH-COORi
    CH- R3R2L
    where Ri and PZ are the same or different and mean lower alkyl, 15 when heated in an inert low boiling organic solvent in the presence of a base, followed by reacting the product thus obtained with cyclopropylamine of formula IV 20
    fc
    sh.
    in an inert organic solvent medium at 70-100 ° C, cyclizing the product obtained in this way in an inert organic solvent medium when heated in the presence of a base, followed by saponification and precipitation of the target product with an acid, distinguishes
    ten
    15 20
    25
    thirty
    so that, in order to intensify the process while maintaining a high yield of the target product, the interaction of the compounds of formulas (II) and (III) is carried out by adding the compound of formula (II) to the mixture of the compound of formula (III), an inert low boiling organic solvent and base at 90-110 ° C or its boiling point, and the cyclization is carried out in an environment of inert high-boiling organic solvent at 135-145 ° C, all stages being carried out without isolating the corresponding reaction product.
    [2]
    2. Method pop. 1, characterized in that the low boiling point solvent is removed before adding cyclopropylamine.
    [3]
    3. A process according to claim 1, characterized in that the low boiling point solvent is removed after reaction with cyclopropylamine.
    [4]
    4. A method according to claim 3, characterized in that the removal is carried out by heating to a cyclization temperature after adding an inert high-boiling organic solvent.
    [5]
    5. A method according to claim 1, characterized in that before the saponification, the reaction mixture is cooled to a temperature in the order of 90-100 ° C.
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    同族专利:
    公开号 | 公开日
    AU602226B2|1990-10-04|
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    JPS6440460A|1989-02-10|
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    UA8018A1|1995-12-26|
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    DE2808070A1|1978-02-24|1979-08-30|Bayer Ag|PROCESS FOR THE PRODUCTION OF 4-PYRIDONE-3-CARBONIC ACIDS AND / OR DERIVATIVES|
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    DE3318145A1|1983-05-18|1984-11-22|Bayer Ag, 5090 Leverkusen|7-AMINO-1-CYCLOPROPYL-6,8-DIFLUOR-1,4-DIHYDRO-4-OXO-3-CHINOLINE CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THEIR CONTAINING ANTIBACTERIAL AGENTS|
    DE3426486A1|1984-07-18|1986-01-30|Bayer Ag, 5090 Leverkusen|METHOD FOR PRODUCING CHINOLONIC AND NAPHTHYRIDONE CARBONIC ACIDS|
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    DE3441788A1|1984-11-15|1986-05-15|Bayer Ag, 5090 Leverkusen|ALKYL-1-CYCLOPROPYL-1,4-DIHYDRO-4-OXO-3-CHINOLINE CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THE ANTIBACTERIAL AGENTS CONTAINING THEM|
    JPS6259263A|1985-09-10|1987-03-14|Kyorin Pharmaceut Co Ltd|Quinolonecarboxylic acid derivative|US5093515A|1987-08-14|1992-03-03|Asahi Glass Company Ltd.|Fluorinated benzoyl compounds|
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    US6531624B1|1998-11-18|2003-03-11|Asahi Glass Company Ltd.|Aminoacrylic acid derivatives and process for producing the same|
    US20080139574A1|2006-11-30|2008-06-12|Cadila Healthcare Limited|Novel quinoline derivatives|
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    法律状态:
    2005-03-20| REG| Reference to a code of a succession state|Ref country code: RU Ref legal event code: PC4A Effective date: 20050118 |
    优先权:
    申请号 | 申请日 | 专利标题
    DE19873724466|DE3724466A1|1987-07-24|1987-07-24|PROCESS FOR THE PREPARATION OF CHINOLON CARBOXYANESE|
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